This invention is directed to a method and system for treating a patient""s heart with therapeutic or diagnostic agents. More particularly, it involves a means to form channels in desired layers of the heart muscle, the epicardium, endocardium and myocardium, and means to deliver therapeutic or diagnostic agents into the channels.
Targeted delivery of therapeutic or diagnostic agents is a desirable but often difficult goal. Potential benefits include efficient use of the agent and limitation of agent action to the desired area. However, the problems that must be overcome are significant: access, transporting the agent to the desired area of the patient; minimization of systemic loss, keeping the agent within the desired area; and timing, ensuring a sufficient quantity of the agent is available in the desired area for sufficient period of time to achieve the therapeutic or diagnostic effects.
One promising strategy for agent delivery involves somtatic gene therapy. Cells in a desired region of the body are engineered to express a gene corresponding to a therapeutically or diagnostically useful protein. Genetic information necessary to encode and express the protein is transferred to the cells by any of a number of techniques, including viral vectors, electroporation, receptor-mediated uptake, liposome masking, precipitation, incubation and others. Gene therapy can be a direct in vivo process where genetic material is transferred to cells in the desired region of the patient""s body. Most current in vivo strategies rely on viral vectors. Alternatively, the process can be an indirect in vitro process where cells from the desired region are harvested, genetic material is transferred to the cells, and the cells are implanted back in the patient""s body. In vitro techniques allow for more flexibility in transfer methods and may be safer since viral vectors need not be introduced into the patient""s body, thus avoiding the theoretical risk of insertional mutations, replication reactivation and other harmful consequences. However, not all tissues are susceptible to harvesting and implantation and require an in vivo technique. The engineered cells can secrete the protein for a significant period of time, ensuring its supply in the target region. Human adenosine deaminase was expressed in vivo by rat vascular smooth muscle cells for over six months. Lynch C M et al., Proc. Natl. Acad. Sci. USA 89:1138-42 (1992).
One region of interest for gene therapy is the circulatory system. Researchers have transferred genetic material to the vascular walls, particularly the smooth muscle and endothelial cells. Suitable delivery techniques include ligation of the vessel (Lynch et al., supra.), dual-balloon catheters (Leclerc G et al., J. Clin. Invest. 90:936-44 (1992)), perforated balloon catheters (Flugelman M Y et al., Circulation 85:1110-17 (1992)), stents seeded with transduced endothelial cells (Dichek D A et al., Circulation 80:1347-53 (1989)) and vascular grafts lined with transduced endothelial cells (Wilson J M et al., Science 244:1344-46 (1989).
However, these methods have not been found suitable for treatment of the heart muscle. Thus far, experimental gene therapy in rats has been achieved through direct injection of DNA into the mvocardium. Lin H et al., Circulation 82:2217-21 (1992) and Acsadi G et al., New Biologist 3:71-81 (1991). In these studies, direct injection caused inflammation, apparent myocyte necrosis and scar tissue along the needle tracks. When compared to injection of plasmid DNA, gene transfer by injection of adenovirus vectors was markedly more efficient. Guzman R G et al., Circulation Research 73:1202-7 (1993). Gene transfer using adenovirus vectors injected into pig hearts was highly efficient in regions immediately adjacent the injection, but evidence of gene transfer was found only within 5 mm of the injection. French B A et al., Circulation 90:2414-24 (1994). As in the studies above, a prominent inflammatory response was associated with the injection. There remains a need for effective gene therapy methods for the heart.
Another difficulty associated with gene therapy is the need to transfer an effective amount of the genetic material in a clinically relevant time period. Exemplary techniques for introduction of engineered endothelial or smooth muscle cells or for in vivo gene transfer require total occlusion of the vessel for 30 minutes. Nabel E G et al., Science 249:1285-88 (1990); Nabel E G et al., Science 244:1342-44 (1989); and Plautz G et al., Circulation 83:578-83 (1991). These time frames would not be feasible for delivery involving the heart. A study attempting to shorten these times employed a perforated balloon catheter and successfully delivered retroviral vectors within one minute, but achieved fewer than 100 transduced cells in a two cm segment of tissue. Flugelman et al., supra. Accordingly, there remains a need to provide gene therapy methods that effect sufficient cellular transduction either by providing more rapid transfer rates or by allowing long-term delivery without impermissibly interfering with cardiac function.
Targeted agent delivery that does not rely on gene therapy would also benefit from similar features. It is often desirable to release the therapeutic or diagnostic agent over a period of time. Levy R J et al., WO 94/21237 discloses a system and method for treatment of arrhythmia that involves transmyocardial delivery of time-release antiarrthymic agents by contacting the epicardium, endocardium or pericardium. Levy et al.""s drug compositions generally comprise a biocompatible polymer formulated to release the active agent in a controlled manner, preferably in the form of a patch applied to the exterior of the heart. The reference also suggests various intravascular placement methods including an implantable catheter tip, an expandable system with anchoring prongs or intramyocardial placement via a stab wound with a trocar. Thus, there is also a need for a system for cardiac agent delivery that effectively delivers agent to the heart wall.
This invention is a system for treating a patient""s heart which comprises a means to form channels in the heart wall and a means to deliver a therapeutic or diagnostic agent into the channels. Additionally, the system may comprise a means to retain the agent within the channels for a useful period of time. The system may be configured to be introduced percutaneously for intravascular delivery to form channels from the epicardial surface. Alternatively, the system may be configured for intraoperative use, to be introduced thoracoscopically or through a thoracotomy, to form transmural channels from the epicardial surface. The system generally comprises an elongated, flexible lasing transmission means having a laser radiation emitting means and an agent delivery means on the distal end.
In one embodiment, the system comprises a catheter having an optical fiber with a lens at the distal end disposed in a first lumen, an agent delivery lumen having an opening at the distal end of the catheter and an occlusion balloon disposed adjacent the distal end of the catheter in fluid communication with an inflation lumen. In use, the distal end of the catheter is positioned adjacent a desired area of the heart wall, then radiation is transmitted through the optical fiber and emitted through the lens to form a channel in the myocardium. The distal end of the catheter is advanced into the channel and the occlusion balloon inflated. The agent is introduced into the channel through the delivery lumen and is retained by the occlusion balloon.
In another embodiment, the system comprises an optical fiber with a lens at tire distal end slidably disposed within a catheter. The distal end of the catheter is connected to the distal end of the fiber by a flexible tube which presents a delivery surface. Agent is coated along the outside of the tube. In preparation for delivery, the optical fiber is moved proximally relative to the catheter to cause the tube to invert, shielding the agent. Once the channel is formed, the optical fiber is moved distally relative to the catheter to evert the delivery surface of the flexible tube. In such embodiments, the means to retain the agent within the channel for a useful period of time may comprise use of a viscous carrier, such as a biocompatible polymer matrix or a carrier which can become or be made highly viscous in situ to affect the kinetics of the agent and host cell interaction to improve the efficacy of the agent.
In another embodiment, the system comprises a multi-lumen catheter having a central agent delivery lumen and a plurality of lumens positioned radially around the central lumen, having an optical fiber with a lens on the distal end disposed in each.
In yet another embodiment, the system comprises a catheter with a optical fiber having a lens on the distal end disposed within a lumen. The lumen is sealed at the distal end and has a plurality of delivery ports on the catheter""s sidewall adjacent the distal end which are in fluid communication with the lumen. Once the distal end of the catheter has penetrated the heart wall, agent is delivered through the lumen and out the ports.
Practice of the invention comprises forming channels in the heart wall and delivering a therapeutic or diagnostic agent into the channel. Gene therapy agents of this invention comprise vectors for transferring genetic information to the heart tissue in vivo or harvested cells which have been genetically engineered in vitro. Additionally, the invention may comprise retaining the agent within the channels, for example, by incorporating the agent in a viscous carrier.
Channel forming means other than laser radiation transmitting means are suitable. Examples of useful means include thermal ablation means, radiofrequency ablation means, rotating tissue removal means, water jet removal means and ultrasonic ablation means.